We have developed an immunotoxin SS1P that targets ovarian cancers, mesotheliomas and pancreatic cancers that is currently in clinical trials. We are carrying out laboratory experiments to produce improved forms of SS1P. One approach is to modify SS1P with high molecular weight polyethylene glycol to decrease immunogenicity and increase half-life in the circulation. Many mutants of SS1P have been produced to allow site-specific modification with PEG. Several of these have been modified with PEG and have good anti-tumor activity in mice. Hematopoietic Tumors- Immunotoxin BL22 has shown excellent clinical activity in patients with Hairy Cell Leukemia. To increase the usefulness of BL22 in other leukemias and lymphomas we have mutated the protein to increase its affinity for CD22 and also mutated the toxin to increase its ability to reach the cytosol and kill target cells. An improved form of BL22 called HA22 has been licensed to Cambridge Antibody Technology who will sponsor trials in various B cell leukemias and lymphomas. Other high affinity forms of BL22 are now being prepared. The IRTA2 gene is expressed in many lymphomas. We have prepared monoclonal antibodies to IRTA2 and shown that the protein is expressed on the surface of myelomas and several B cell leukemias and lymphomas. We have used these MAbs to develop an ELISA for IRTA2. Soluble IRTA2 protein is present in human serum and its levels are elevated in Hairy Cell Leukemia and other leukemias and lymphomas. We are exploring new ways to enhance immunotoxin action. We have found that immunotoxins synergize with several chemo therapeutic agents in animal models.